Adefovir dipivoxil is an antiviral nucleotide analog, showing excellent effect as a therapeutic agent for HIV infection and hepatitis B virus (HBV) infection. The antiviral activity of said compound is shown in the references (for example, see U.S. Pat. Nos. 4,724,233 and 4,808,716; EP Patent No. 0 481 214; Benzaria et al., “Nucleosides and Nucleotide” 14(3-5):563-565, 1995; and Starrett et al., J. Med. Chem. 37:1857-1864, 1994).
The chemical structure of adefovir dipivoxil is seen in the following formula 1:

Adefovir dipivoxil was first disclosed in EP Patent No. 0 481 214 and may exist in amorphous or crystalline forms. The amorphous form of adefovir dipivoxil can be obtained by eluting from a silica gel column using a mixture of methanol (about 4%) and methylene chloride (about 96%), and precipitating by rotary evaporation under reduced pressure at about 35° C. (see J. Med. Chem., 19:1857-1864, 1994). However, the purification and preparation of an amorphous form have the disadvantages that the procedures are not suitable for application to mass production and the amorphous form must be protected from heat, light, oxygen and moisture. Thus, as an alternative method, the crystal forms of adefovir dipivoxil were prepared and used. As an example thereof, WO04/043972 discloses a spray-drying process wherein directly prepared or commercially available adefovir dipivoxil is dissolved in an organic solvent and sprayed as micro droplets of drug solution under a high-temperature stream, and thus obtained droplets are immediately dried to give crystals. However, this method has the disadvantage of using a spray-dryer device that is not suitable for mass production. On the other hand, U.S. Pat. No. 6,451,340 discloses a method of preparing Form 2 (2 hydrate) by diluting adefovir dipivoxil solution containing 0.2% or less of water and 50% or more of 1-methylpyrrolidinone with acetone, adding n-butyl ether to produce a crystal, cooling to give Form 1, contacting said Form 1 with air having 75% or more of relative humidity or crystallizing it from a solvent containing 2-5% of water. However, this method uses a dangerous and explosive organic solvent such as n-butyl ether as the crystallizing solvent.
Polymorphism is generally considered to mean separate solids having the same molecular formula but different physical properties in melting point, solubility, density, etc. The differences in physical properties of polymorphs come from the alignments of adjacent molecules (complexes) and interactions between molecules in a bulk solid. Thus, polymorphs having the same molecular formula are unique solids in that it is not clear whether one polymorph has more advantageous physical properties than another. One of the most important physical properties of a pharmacological polymorph is water solubility, particularly solubility in the gastric juice of a patient. For example, when absorption through the intestinal tract is slow, it is desirable that the drug which is unstable under the circumstance of the stomach or intestine of a patient is slowly dissolved and not to be accumulated under this harmful circumstance. Such crystal compounds may have different fluidity, elastic deformability, dissolution rate in a pharmaceutical preparation, stability, efficacy, etc. Thus, a crystal form that is more stable, easier to handle and has a high dissolution rate is required in the art. That is, discovery of a novel crystal form of a drug would enable a skilled artisan in the field of formulation to design a pharmaceutical formulation of a drug having the desired release profile or other characteristics.
Therefore, the present inventors tried to provide a variety of novel crystal forms of adefovir dipivoxil to broaden the range of choice in preparing a pharmaceutical composition as well as to resolve the problems of the prior art in preparing the novel crystal forms.
Thus, it is one object of the present invention to provide novel crystal forms of adefovir dipivoxil.
Another object of the present invention is to provide processes for the preparation of the novel crystal forms of adefovir dipivoxil.